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CDK2AP1 and Carcinogenesis. First discovered as a tumor suppressor gene in oral cancer, CDK2-AP1 exerts its growth suppressor function by negatively regulating the activities of DNA polymerase-a/primase 3 and cyclin-dependent kinase 2 (CDK2). CDK2-AP1 associates with DNA polymerase-a/primase suppressing DNA replication, affecting predominantly the initiation step. CDK2-AP1 has been found to associate with the monomeric non-phosphorylated form of CDK2, suppressing CDK2-associated kinase activities and cell cycle progression. CDK2-AP1 also targets CDK2 for proteolysis. We are investigating the detailed biochemical and genetic mechanisms of CDK2-AP1 in cell cycle regulation, normal development and carcinogenesis. Recent excitement of this research includes the discovery that CDK2-AP1-nulled mice are embryonically lethal and that CDK2-AP1 is an epigenetic regulator for differentiation competency for mouse embryonic stem cells, placing this gene at a pivotal juncture of stem cell differentiation and development; CDK2AP1 is a competency factor in the proper differentiation of mESCs by modulating the phosphorylation level of pRb; that Cdk2ap1, a negative regulator of Cdk2 function and cell cycle, promotes Oct4 promoter methylation during murine embryonic stem cell differentiation to down-regulate Oct4 expression. We further show that this repressor function of Cdk2ap1 is dependent on its physical interaction with the methyl DNA-binding protein, Mbd3, supporting a molecular link between the known differentiation promoters, including bone morphogenetic proteins and transforming growth factor signaling, and embryonic stem cell differentiation. Recently we have further demonstrated that CDK2-AP1-mediated epigenetic control via Mbd3/NuRD (nucleosome Remodeling and Deacetylation) complex regulates Wnt signaling genes, which plays an important role in ESC maintenance and differentiation. CDK2AP1 is a critical tumor suppressor gene with significant implications in cancer research. Its discovery as a gene frequently deleted in oral cancer has led to a deeper understanding of its role in cell cycle regulation, apoptosis, differentiation, and epigenetic modification. The study of CDK2AP1 continues to inform the development of diagnostic markers and targeted therapies, highlighting its importance in the fight against cancer.

Salivaomics, Saliva-Exosomics and Saliva Liquid Biopsy. We coined the term "Salivaomics," which encompasses the comprehensive study of saliva's molecular constituents. Our research has shown that saliva contains valuable biological information for disease detection and monitoring. We have also made significant contributions to the study of exosomes in saliva, demonstrating their potential for identifying biomarkers for various diseases. Additionally, our studies in developing saliva-based liquid biopsy techniques, particularly with EFIRM technology, has enabled the early detection and monitoring of cancer. Our research has led to the development of saliva-based tests for early detection of oral, lung and gastric cancers, and he has contributed to the identification and validation of comprehensive biomarker panels in saliva for various diseases. Overall, his work has the potential to revolutionize healthcare by providing a non-invasive and accessible means of early cancer detection and monitoring.

EFIRM Liquid Biopsy. EFIRM (Electric Field-Induced Release and Measurement) Liquid Biopsy is an innovative technology for detecting biomarkers from bodily fluids, like blood or saliva, to diagnose and monitor diseases, particular for early detection of cancer. It leverages electric fields to release and measure extracellular vesicles and other biomarkers without extensive sample preparation. Key features include non-invasiveness, direct detection (no sample processing) rapid detection, cost-effectiveness, and versatility for various diseases. In cancer detection, EFIRM Liquid Biopsy is valuable for early

detection, disease progression monitoring, treatment response evaluation, and detecting minimal residual disease and recurrence. The performance of EFIRM towards detection of ctDNA surpasses digital PCR and next generation sequencing. It involves sample collection, electric field application, and biomarker measurement, offering advantages over traditional methods such as reduced invasiveness, faster results, and dynamic disease monitoring. Ongoing research aims to explore EFIRM Liquid Biopsy's potential to improve cancer diagnostics and patient management. Studies focus on its efficacy in detecting specific cancer types like lung, head and neck, breast, and colorectal cancers and its ability to track treatment efficacy and disease recurrence.